Effects of 5-HT1A receptor antagonists on fluoxetine-induced changes in extracellular serotonin concentrations in rat frontal cortex
Introduction
The involvement of serotonin (5-hydroxytryptamine, 5-HT) in the pathogenesis of depression and its mechanistic role in the action of antidepressant drugs has been well established (Delgado et al., 1990; Briley and Moret, 1993). The most direct evidence for this has come from the clinical efficacy of the serotonin specific reuptake inhibitors in the treatment of depression. These drugs exert their action by increasing the concentration of serotonin within the synaptic cleft by blocking its transport/reuptake and, hence enhancing serotonergic transmission (Hyttel, 1994). However, the onset of antidepressant activity requires a period of chronic treatment before this activity can be observed, usually 2–4 weeks (Blier and De Montigny, 1994; Gardier et al., 1996). Electrophysiological data has demonstrated the desensitization of presynaptic serotonin receptors during chronic treatment with serotonin specific reuptake inhibitors (Blier et al., 1987) and microdialysis studies have also shown an enhancement in extracellular serotonin following chronic treatment (Rutter et al., 1994; Invernizzi et al., 1996). This would suggest that the delayed onset of action of serotonin specific reuptake inhibitors is due to the action of the inhibitory somatodendritic serotonin receptors in response to the serotonin specific reuptake inhibitors-induced increases in extracellular serotonin. Clinical data using co-administration of a serotonin specific reuptake inhibitors with the β-adrenoceptor/5-HT1A receptor antagonist pindolol, in small open trial studies, has demonstrated a shortened time to onset of antidepressant activity (Artigas et al., 1994; Blier and Bergeron, 1995) which has been attributed to the antagonist effects of pindolol at the presynaptic 5-HT1A receptor, thus preventing desensitization. Conversely, more recent data using double blind clinical trials (Berman et al., 1997; Perez et al., 1997) has demonstrated little or no improvement in antidepressant activity. It is therefore clear that this is still an area of controversy.
The present study demonstrates how blockade of the somatodendritic 5-HT1A receptor with the selective and silent antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide (WAY100635) (Forster et al., 1995) can potentiate acute fluoxetine-induced changes in extracellular serotonin concentrations in the frontal cortex of the rat. The relative degrees of blockade of both the 5-HT1A receptor versus the serotonin transporter have also been analyzed. A range of antagonists/agonists were chosen due to their differing degrees of intrinsic agonist activity for the 5-HT1A receptor. These compounds were: N-tert-butyl 3-4-(2-methoxyphenyl)piperazin-1-yl-2-phenylpropananamide dihydrochloride ((+)-WAY100135), a partial agonist (Escandon et al., 1994; Assie and Koek, 1996) with low detectable intrinsic activity (Routledge et al., 1993), 8-[4-[4-(2-pyrimidinyl)-1-piperazinyl]-8-azaspiro[4.5]decane-7,9-dione (buspirone), a known partial agonist (Sprouse and Aghajanian, 1987), and (R)-N-[2-[4[(1H-indol-4-yl)-1-piperazinyl]-1-methylethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY101363), a partial agonist with high antagonist affinity (Sukoff and Rosenzweig-Lipson, 1997) but detectable agonism. Using these compounds we have determined that only compounds with very low intrinsic agonist activity can produce a potentiation of these fluoxetine-induced increases in serotonin in the frontal cortex.
Section snippets
Materials and methods
All chemicals used were analytical grade and were purchased from Aldrich and Sigma chemicals (Milwaukee, WI). Buspirone was purchased from Research Biochemicals International (Natick, MA). WAY100635, WAY101363 and (+)-WAY100135 were synthesized by Chemical Sciences, Wyeth Ayerst Research (Princeton, NJ).
Effects of fluoxetine concentration on WAY100635-induced potentiation of extracellular serotonin concentrations
In order to determine the effects of increasing serotonin transporter blockade on extracellular serotonin concentrations following antagonism of the 5-HT1A receptor, animals were administered with WAY100635 (1 mg/kg, s.c.) followed by the serotonin specific reuptake inhibitor fluoxetine (3–20 mg/kg, s.c.) (Fig. 1). WAY100635 alone had no effect on extracellular serotonin concentrations. The lowest dose of fluoxetine (3 mg/kg) alone and in the presence of WAY100635, produced no significant
Discussion
Administration of single doses of the serotonin specific reuptake inhibitor, fluoxetine (5–20 mg/kg) did not produce significant increases in extracellular serotonin levels in the frontal cortex. The effects of fluoxetine were not dose-related and reached a maximum value of only 125% after 20 mg/kg; however, it should be noted that as the dose increased the response became more variable indicating some evidence of a dose-relationship. These observations are consistent with acute systemic
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